tbuckley/cabot-search huggingface dataset:
P11.18.B AIMING TOWARDS DIFFERENTIATING GLIOBLASTOMA PROGRESSION FROM PSEUDO PROGRESSION -PATIENTS COHORT ESTABLISHMENT AND PRELIMINARY RESULTS
Authors: O Haisraely, A Taliansky, T Kaisman elbaz, H Abofani, M Siddeeq
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Longitudinal follow-up of glioblastoma patients includes advanced imaging modalities to identify tumor progression, which is of limited certainty and occasionally necessitates additional tissue sampling that has potential morbidity. Lately, the possibility of tumor-associated protein markers detection in patients' blood samples - liquid biopsies - has shown useful for this purpose in other cancers and has also gained significant interest in glioblastoma. METHODS This study presents data collected from 36histopathology-confirmed IDH-WT glioblastoma patientstreated in Sheba Medical Center between the years 2009 to 2021. Following their diagnosis, these patients were treated with radiation according to the Stupp protocol and subjected to repeated resection due to suspected tumor progressionbased on imaging studies. The data retrieved from patients' medical files include demographics, clinical outcomes, imaging characteristics, tumor molecular, andhistopathological markers. Notably, patients' selection and data retrieval were accomplished using a novel institutional AI algorithm software followed by complementary manual data retrieval of selected patients' medical files. RESULTS Patients demographics analysis showed that patientmedian age-at-diagnosis was 55.4 years (range, 21-82), and the male-to-female ratio was 3.5:1. The median overall survival (OS) was 25.1 months (range, 5.2-80.3) and the median follow-up duration was 23.1 months (range, 4.8-80.2).27 out of 36 patients had pathologically confirmed tumor progression while the remaining patients had post-radiation changes along with viable tumor or merely radiation necrosis identification. Pre-surgical resection blood samples were available for 27 out of 37 patients and will be used for a comprehensive glioblastoma-related proteins search using mass spectroscopy. In cases of patients' blood samples available both from the initial diagnosis surgical resection procedure and tumor progression surgical resection, a comparative analysis of those samples will be performed. The preliminary proteomics analysis and clinical outcomes measurements and volumetric tumor data will be presented. CONCLUSION s: Here, we present a glioblastoma patient cohort that was meticulously selected with the aim to examine our hypothesis that measuring glioblastoma-related proteins in patients' blood can be achieved and serve as a tool to distinguish between disease phases and monitor disease progression. Our comprehensive preliminary clinical, as well as proteomics data analysis, will be presented and discussed.
JS08.5.A VEGFR2-SPECIFIC CAR T CELLS WITH ANTI-GLIOMA AND ANTI-ANGIOGENIC ACTIVITY AGAINST GLIOBLASTOMA
Authors: M Mastall, D Villars, M Silginer, C Rössig, T Weiss, M Weller, P Roth
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Chimeric antigen receptor (CAR) T cell therapy has emerged as a potent immunotherapy against hematological malignancies. In glioblastoma, however, limited infiltration of the tumor by CAR T cells, tumor heterogeneity, antigen escape and an immunosuppressive tumor microenvironment remain significant obstacles. Vessel-targeting CAR T cells have been shown to infiltrate solid tumors more efficiently and have the additional benefit of co-targeting the tumor vasculature with genomic stability. Therefore, vascular endothelial growth factor receptor 2 (VEGFR2)-CAR T cells may represent a promising strategy by targeting the tumor vasculature as well as VEGFR2-expressing tumor cells. Here, we explored the efficacy of VEGFR2-specific CAR T cells against experimental gliomas as well as the contribution of anti-tumor and anti-vasculature-dependent effects of this strategy. METHODS Tissue microarrays of glioblastoma patients (n=113) were stained for VEGFR2 expression. Human CAR T cells were generated by lentiviral transduction to express a second generation CAR construct against either mouse or human VEGFR2 (mVEGFR2 or hVEGFR2). Their activity was assessed in co-culture assays in vitro against murine endothelial and human glioma cells, respectively. Several orthotopic xenograft mouse glioma models were used to test the in vivo activity of the newly generated CAR T cells. RESULTS We confirmed high VEGFR2 expression on endothelial cells in glioblastoma tissue of stained tissue microarrays as well as in 20.3% of tissue samples also on tumor cells. In co-culture assays, hVEGFR2-CAR T cells were exclusively active against human glioma cells and mVEGFR2-CAR T cells against mouse endothelial cells, respectively. The specificity of hVEGFR2-CAR T cells was confirmed by a CRISPR/Cas9-mediated knockout of hVEGFR2 in a human glioma cell line. In all three in vivo glioma models, intratumoral treatment of hVEGFR2-CAR T cells significantly prolonged the survival of glioma-bearing mice and cured a substantial fraction of these animals in one model. Additionally, we found that survival was prolonged after mVEGFR2-CAR T cell treatment in one glioma model, which correlated with high vascularization of these tumors. CONCLUSION Our dataset demonstrates that VEGFR2-CAR T cells prolong the survival of glioma-bearing mice through anti-glioma and anti-glioma vasculature activity. The results suggest that the magnitude of the vasculature-targeting activity depends on vessel-density within the tumor. VEGFR2 might be a relevant target that could be exploited for a novel CAR T cell-based immunotherapeutic approach against glioblastoma.
OS07.5.A GLIOBLASTOMA VESSEL CO-OPTION AND TRANSITION TO A RESISTANT CELL STATE ARE INDUCED BY CHEMORADIATION
Authors: C Pichol-Thievend, O Anezo, A M Pettiwala, G Bourmeau, R Montagne, A Lyne, P Guichet, P Deshors, A Ballestín, B Blanchard, J Reveilles, V M Ravi, K Joseph, D H Heiland, B Julien, S Leboucher, L Besse, P Legoix, F Dingli, S Liva, C Furumaya, L Kovandzic Marcos, K Masliantsev, T Daubon, O Schnell, J Beck, N Servant, L Karayan-Tapon, F M G Cavalli, G Seano
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GB) is one of the deadliest types of human cancer. Despite a very aggressive treatment regime, including resection of the tumor, radiation, and chemotherapy, the recurrence rate is more than 90%. Recurrence is mostly caused by the regrowth of highly invasive and resistant cells that have spread from the tumor bulk and are not removed by resection. To develop an effective therapeutic approach, we need to better understand the underlying molecular and cellular mechanisms of GB chemoradiation resistance and tumor spreading. MATERIAL AND METHODS To dynamically follow the changes occurring in GB post-therapy and investigate its relationship with vascular microenvironment, we employed multiple bulk and single-cell RNA-Seq analyses, phosphoproteome, in vitro and in vivo real-time imaging, organotypic cultures and functional assays, digital pathology, and spatial transcriptomics on patient material or preclinical models of GB. RESULTS We demonstrated that chemoradiation and the brain vasculature induce a transition to a functional cell state, which we named VC-Resist. This cell state is midway through the transcriptomic axis between proneural and mesenchymal GB cells and is closer to the AC/MES-like state. Better cell survival, G2M-arrest, activation of senescence/stemness pathways make this GB cell state more resistant to therapy. Notably, these persister GB cells are highly vessel co-opting, allowing homing to the perivascular niche, which, in turn, increases their transition to this cell state and resistance to therapy. Molecularly, the transition to the VC-Resist cell state is driven by FGF-FGFR1 signaling, which leads to the activation of DNA damage repair and YAP1 pathways. CONCLUSION These findings demonstrate that the perivascular niche and GB cell plasticity jointly generate a vicious loop that leads to resistance to therapy and brain infiltration during GB recurrence. SUPPORT This work was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 (Grant Agreement No. 805225), the INSERM-CNRS ATIP-Avenir grant, the NanoTheRad grant from Paris-Saclay University, Fondation ARC pour la recherche sur le cancer, Campus France and Canceropole Ile-de-France (2022-1-EMERG-06-ICR-1).
P14.12.A PLASMA CFDNA LIQUID BIOPSY IN THE FOLLOW-UP OF HIGH-GRADE GLIOMAS
Authors: V Pieri, G Berzero, R Paterra, Q D'Alessandris, G Sferruzza, E Pompeo, F Roncelli, G Nocera, M Bailo, L Barzaghi, A Castellano, A Falini, P Mortini, R Galli, G Finocchiaro, M Filippi
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND As highlighted by the 2021 WHO classification of brain tumors, molecular characterization of gliomas is now critical to complement histopathological evaluation. However, intratumor heterogeneity may lead to surgical specimens not being fully representative of the whole tumor. Moreover, given the invasiveness of surgery, tissue analyses are not repeatable over time, thus limiting the possibility to monitor the response to therapies. In this context, we investigated the potential value of plasmatic cell-free DNA (PcfDNA) as a non-invasive ‘liquid biopsy’ marker of disease evolution. MATERIAL AND METHODS Patients’ blood was collected at 4 time points (TP), in parallel to clinical follow-up. A reproducible pipeline was optimized for blood withdrawal, centrifugation, plasma storage, cfDNA extraction from plasma by QIAamp MinElute ccfDNA Midi Kit (Quiagen) and cfDNA fluorometric quantification by Qubit (Thermo Fisher Scientific). MRI volumes were segmented in T1+contrast and T2-FLAIR sequences. RESULTS Fifty-four high-grade glioma patients and 14 healthy controls were enrolled. Blood samples were collected from all 54 patients at radiological diagnosis before surgery (TP0), from 33 patients after surgery (TP1), from 21 patients after radio-chemotherapy(TP2), from 10 patients at the first radiological progression (TP3). At T0, a significantly higher concentration of PcfDNA was detected in patients than in controls. IDH-wild-type gliomas showed a trend toward higher PcfDNA when compared with IDH-mutant gliomas. Digital-droplet PCR, performed at T0on PcfDNA of 4 patients with IDH-mutations in tumor tissues, identified the same IDH1-R132H mutation in all cases. When PcfDNA at TP0 was compared to that at TP1 of the same patient (n=33), there was a significant reduction of plasmatic cfDNA after surgery, mirroring the extensive tumor-resection shown by MRI. Finally, PcfDNA was evaluated in 10 patients until their radiological progression. Interestingly, PcfDNA levels not only followed the same trend of the volumes of T2-FLAIR hyperintensities and T1 contrast-enhancements, but were also mirrored by the evolution of KPS and NANO scores. CONCLUSION Preliminary results suggest that PcfDNA content may be an informative tool to complement MRI during the follow-up of high-grade gliomas.
P11.24.B PRELIMINARY RESULTS OF THE TRAIN STUDY: TRAMETINIB IN NEUROFIBROMATOSIS TYPE 1 RELATED SYMPTOMATIC PLEXIFORM NEUROFIBROMAS
Authors: D C Noordhoek, S A van Dijk, P J French, E A C Wiemer, J Visser, A Moelker, O C Manintveld, M J van den Bent, W Taal
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND About half of the patients with neurofibromatosis type 1 (NF1) have plexiform neurofibromas (PN). PNs can cause pain, neurological deficit and cosmetic problems. The current standard treatment of PN is surgery, which is often difficult due to invasive growth and vascularisation. Recent data suggests promising effect of MEK inhibition on symptomatic PN in NF1. MATERIAL AND METHODS We started an open-label, single arm, phase 2 trial of trametinib 2 mg daily in 30 adults with NF1 and at least one symptomatic inoperable PN. The primary outcome measure is decrease in tumor volume of the PN target lesion, as measured on MRI every 6 months. A decrease of ≥20% will be considered as treatment response. The secondary outcome measures are pain, disfigurement, safety and toxicity. RESULTS Seventeen patients have been enrolled between July 2020 and July 2022 with an average follow-up duration of 16 months. In the 15 patients with at least 6 months follow-up, the average numeric pain rating scale (NRS-11) was reduced in 10/15 patients (67%) and a reduction of at least 3 points on the NRS-11 was achieved in 6/15 patients (40%). Tumor volume measurements have been completed in one patient with a PN in the left shoulder region. Tumor volume decreased from 160 cm3 to 100 cm3 (38%) after 18 months of treatment. The most common side effect was acneiform rash, which was present in 11/17 patients (65%). Four patients discontinued treatment permanently, 3 because of toxicity (acneiform rash (2) and CPK increase (1)) and one because of increased pain. Four cases of grade 3 adverse events have been reported: acneiform rash (2), hypertension (1) and asparatate aminotransferase increase (1). The only severe adverse event related to treatment was CPK increase grade 4, for which the patient was hospitalised for diagnostic work-up. Toxicity resolved completely in all patients after discontinuation of treatment. CONCLUSION From these preliminary results we can conclude that trametinib has a beneficial effect on PN related pain. Side effects are mild and toxicity resolved after discontinuation of treatment. At least one patient had a decrease in tumor volume of ≥20%.
P04.03.B VENOUS THROMBOEMBOLISM AND OTHER VASCULAR COMPLICATIONS IN PAEDIATRIC PATIENTS FOLLOWING CRANIOPHARYNGIOMA SURGERY: A SINGLE-CENTER, RETROSPECTIVE STUDY
Authors: B Castelli, M Scagnet, F Mussa, C Fonte, M Di Nicola, M Guidi, M Tellini, L Genitori, I Sardi, S Stagi
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Craniopharyngioma (CP), although slow growing and histologically benign, carries considerable morbidity, particularly in the postoperative period: hypothalamus-pituitary dysfunction and electrolyte disorders represent common complications. Moreover, in these patients, the increased risk of deep venous thrombosis (DVT) and the possible development of fusiform intracranial aneurysms are well known. However, data are still poor, especially in the pediatric population. The aim of our study was to describe the occurrence and timing of DVT and other vascular alterations in neurosurgical operated CP patients and to evaluate the role of predisposing factors in the development of post-surgical and late vascular events. MATERIAL AND METHODS This was a single-center, retrospective study. We investigated 19 patients (11 males, 8 females, mean age 10.47±4.29) diagnosed with CP, who had been subjected to neurosurgery between December 2016 and August 2022 in Meyer Children’s Hospital IRCCS in Florence. Demographic and clinical characteristics and surgical data were recorded for each participant. RESULTS Five patients (26.3%, 3 females, 2 males, median age 15 years) presented vascular events, all during sodium imbalance. Calcium at lower limits was detected in four of them. Three DVT (two with associated pulmonary embolism, including one female patient’s death) developed after surgery, more frequently at 7-10 days (two patients were central catheter carriers, one obese patient showed hypercholesterolemia and hypertriglyceridemia). In a patient in hyponatraemic state a vascular parietal alteration compatible with pseudoaneurysm was described soon after neurosurgery, requiring vascular stenting and prolonged intensive care. Superficial vein thrombophlebitis was a late complication in an overweight female patient on estrogenic replacement therapy. CONCLUSION Patients with CP undergoing neurosurgical brain tumor resection are at a higher risk of developing DVT and vascular alterations, thus careful follow-up should be done in these patients. In our study, we found that the phase of transition from central diabetes insipidus (CDI) to syndrome of inappropriate antidiuretic hormone secretion (SIADH) is probably a significative time for developing this complication; so, we recommend careful monitoring of symptoms suggestive of vascular events in CP operated patients. However, we suggest the execution of a deep vein ultrasound examination in the post-neurosurgical two-four weeks for an early diagnosis of this problem for reducing the risk of severe complications.
OS03.5.A MULTI-ANCESTRY GENOME-WIDE ASSOCIATION STUDY OF 4,069 CHILDREN WITH GLIOMA IDENTIFIES 9P21.3 RISK LOCUS
Authors: J Foss-Skiftesvik, S Li, A Rosenbaum, C M Hagen, U K Stoltze, S Ljungqvist, U Hjalmars, K Schmiegelow, L Morimoto, A J De Smith, R Mathiasen, C Metayer, D M Hougaard, B Melin, K M Walsh, J Bybjerg-Grauholm, A M Dahlin, J L Wiemels
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND While recent sequencing studies have revealed that 10% of childhood gliomas are caused by rare germline mutations, the role of common variants is undetermined and no genome-wide significant risk loci for pediatric CNS tumors have been identified to date. MATERIAL AND METHODS Meta-analysis of three population-based genome-wide association studies (GWASs) comprising 4,069 children with glioma and 8,778 controls of multiple genetic ancestries. Replication was performed in a separate case-control cohort. Quantitative trait loci analyses and a transcriptome-wide association study were conducted to assess possible links with brain tissue expression across 18,628 genes. RESULTS Common variants in CDKN2B-AS1 at 9p21.3 were significantly associated with astrocytoma, the most common subtype of glioma in children (rs573687, p-value 6.974e-10, OR 1.273, CI95 1.179-1.374). The association was driven by low-grade astrocytoma (p-value 3.815e-9) and exhibited unidirectional effects across all six genetic ancestries. For glioma overall, the association approached genome-wide significance (rs3731239, p-value 5.411e-8), while no significant association was observed for high-grade tumors. Predicted decreased brain tissue expression of CDKN2B was significantly associated with astrocytoma (p-value 8.090e-8). CONCLUSION In this population-based GWAS meta-analysis, we identify and replicate 9p21.3 (CDKN2B-AS1) as a risk locus for childhood astrocytoma, thereby establishing the first genome-wide significant evidence of common variant predisposition in pediatric neuro-oncology. We furthermore provide a functional basis for the association by showing a possible link to decreased brain tissue CDKN2B expression and substantiate that genetic susceptibility differs between low- and high-grade astrocytoma.
P06.20.B LONG-TERM CLINICAL RESULTS OF 493 CASES OF NEWLY DIAGNOSED GLIOBLASTOMA AND SURVIVAL BENEFIT BY COMBINATION WITH PDT AND AFTV, AIMING TO ESTABLISH NEW STANDARD TREATMENT
Authors: M Nitta, Y Muragaki, T Saito, S Tsuzuki, S Koriyama, A Kuwano, T Kawamata
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma has the worst prognosis of brain tumors. Evidence for improving prognosis by maximal tumor removal is being established, and in recent years, new treatments such as photodynamic therapy (PDT, 2014 in Japan), and TTF therapy (2018) have been approved, the treatment results are improving. In principle, our facility performs maximum tumor removal using intraoperative MRI (iMRI) follow by the standard chemoradiation. Intraoperative PDT and autologous tumor vaccine (AFTV) will be given to desired patients. We retrospectively analyzed the long-term clinical results of the patients with newly diagnosed glioblastoma who underwent surgical treatment at our facility, and the treatment results by era and treatment method. MATERIAL AND METHODS The clinical features, extent of removal (EOR), OS and PFS of the adult patients with newly diagnosed glioblastoma treated from 2001 to 2021 were analyzed retrospectively. Clinical results of those patients who received PDT and AFTV treatment was also investigated. RESULTS The number of cases was 493, median age 58 years (18-85 years), 293 males, 200 females. The median and average EOR of contrast-enhanced lesions were 98% and 96.6%, respectively. The median PFS and OS of all cases (including biopsy) were 9.4 months and 22.7 months, respectively. When the cases were analyzed separately for 2001-2006 (before TMZ), 2007-2010, 2011-2015, and 2016-2021, the median OS for each age group was 12.9 months, 22.9 months, 23 months, and 31.1 months. The treatment results improved with age (p &amp;lt;0.0001). In particular, the median OS of 23 cases treated with PDT and AFTV was 63.1 months. The efficacy of AFTV for newly diagnosed glioblastoma is currently being verified in a multicenter Physician-led clinical trial. CONCLUSION The treatment results for glioblastoma have improved over the years. The combination of maximal tumor removal using iMRI, PDT and AFTV may aim for a 5-year survival rate of 50%.
P18.04.B SINGLE CELL TRANSCRIPTOMIC ANALYSIS IDENTIFIES DISTINCT INTRATUMORAL SUBCLONES IN MENINGIOMA
Authors: C Blume, Y Tang, H Dogan, M Ritter, S Dentro, A von Deimling, M Gerstung, M Schlesner, F Sahm, S L N Maas
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Meningiomas arise from the leptomeninges of the brain and spinal cord. Despite being the most common intracranial tumor in adults, risk stratification remains challenging. Currently, tumors are graded based on histology as well as molecular markers. In recent years, several epigenomic classification systems with a correlation to patient outcome have been proposed for meningiomas. However, these classification systems do not discriminate between effects of the tumor microenvironment and the tumor itself or consider distinct intratumoral subpopulations with different phenotypes. To address this, we set out to investigate intratumoral differences and correlated them with gene expression differences. MATERIAL AND METHODS We applied single nuclei RNA sequencing (10X Genomics 3’) to 30 meningioma samples to obtain transcriptomic profiles on single cell level. Copy number variations were estimated for single cells based on the transcriptomic profiles to identify clonal differences within a given tumor. RESULTS Based on aberrations in the copy number profile, we were able to identify distinct subclones within the same tumor, which could in many cases be connected to a change in the transcriptomic profile of the respective subclone. Different patterns of subclonal diversity were observed between tumor grades. Further insight into the subpopulations was used to infer a novel model for prognostication which was validated by methylation data. CONCLUSION Altogether, these results demonstrate that diverse subclones co-exist within meningioma, especially within higher-grade tumors. Effects of meningioma subclones on tumor growth and their relevance for clinical risk prediction remain to be elucidated.